Pyridopyrimidines as nonclassical antifolates

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Claims

1. A compound of the formula: ##STR12## in which: Q is --OH or --NH.sub.2;

A is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, or --S--;
--Ar-- is a divalent aromatic ring;
W is --CO-- or --SO.sub.2 --; and
Z is:
(A) an.alpha.-amino acid group of the formula ##STR13## wherein * designates a chiral center in the L configuration, n has a value of from 0 to 4, and
R is:
(i) V, wherein V is a tetrazolyl group of the formula ##STR14## where B is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 hydroxyalkyl, or
(ii) --SO.sub.3 H;
(B) a tetrazolyl group of the formula ##STR15## wherein n has a value of from 0 to 4 and E is --COOH or V, wherein V is a tetrazolyl group as defined herein and, if n is greater than 0 or E is other than V, the carbon atom designated * is in the L configuration;
(C) --NHR.sup.1, where R.sup.1 is hydrogen or a substituted or unsubstituted C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl, cycloalkyl, or polycycloalkyl group;
(D) --NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are independently C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl or COOT, where T is hydrogen or C.sub.1 -C.sub.4 alkyl;
(E) ##STR16## where each T is independently as defined previously, n has a value of from 0 to 4, and y has a value of 0 or 1;
(F) ##STR17## where n, T and y are as defined herein, provided at least one y is other than zero;
(G) ##STR18## where n, T and y are as defined herein, provided at least one y is other than zero; or
(H) --NHOH;

7. A compound of the formula: ##STR19## in which Ar is phenylene or thienediyl;

W is --CO-- or --SO.sub.2 --;
Q is hydroxy or amino;
(a) R.sup.2 and R.sup.3 when taken together with the nitrogen atom to which they are attached are a pyrrolidino or piperidino group substituted with one or two groups of the formula COOT in which T is hydrogen or alkyl of 1 to 4 carbon atoms, or
(b) when taken separately, R.sup.2 is hydrogen and R.sup.3 is:
(1) hydroxy,
(2) cycloalkyl of 3 to 8 carbon atoms substituted with --COOT in which T is hydrogen or alkyl of 1 to 4 carbon atoms, or ##STR20## in which E is hydrogen, carboxy, or tetrazolyl and if E is other than hydrogen the configuration about the carbon atom designated * is L,
n has a value of 0 to 4, and
R is
(i) tetrazolyl,
(ii) --SO.sub.3 H,
(iii) glycyl, or
(iv) --CO--J in which J is an.alpha.-amino acid residue of the D-configuration, or provided E is not carboxy, J is hydroxy or alkoxy of 1 to 4 carbon atoms.

8. A compound according to claim 5 in which Q is hydroxy, W is --CO--, and R.sup.2 and R.sup.3 when taken together with the nitrogen atom to which they are attached are a pyrrolidino or piperidino group substituted with one or two groups of the formula COOT in which T is hydrogen or alkyl of 1 to 4 carbon atoms.

11. A compound according to claim 7 in which Q is hydroxy, W is --CO--, R.sup.2 is hydrogen, and R.sup.3 is hydroxy.

13. A compound according to claim 7 in which Q is hydroxy, W is --CO--, R.sup.2 is hydrogen, and R.sup.3 is cycloalkyl of 3 to 8 carbon atoms substituted with --COOT in which T is hydrogen or alkyl of 1 to 4 carbon atoms.

14. A compound according to claim 7 in which Q is hydroxy, W is --CO--, R.sup.2 is hydrogen, and R.sup.3 is --CH(E)(CH.sub.2).sub.n --R in which E is hydrogen, carboxy, or tetrazolyl, n has a value of 0 to 4, and R is tetrazolyl or --SO.sub.3 H.

16. A compound according to claim 7 in which Q is hydroxy, W is --CO--, R.sup.2 is hydrogen, and R.sup.3 is --CH(E)(CH.sub.2).sub.n --R in which E is hydrogen or tetrazolyl, n has a value of 0 to 4, and R is --CO--J in which J is hydroxy or alkoxy of 1 to 4 carbon atoms.

20. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

21. A method of inhibiting the activity of GARFT in a mammal which comprises administering thereto an effective amount of a compound according to claim 1.

22. A method of treating susceptible neoplasms in a mammal which comprises administering thereto an effective amount of a compound according to claim 1.

23. A method of treating psoriasis in a mammal which comprises administering thereto an effective amount of a compound according to claim 1.

24. A method of treating arthritis in a mammal which comprises administering thereto an effective amount of a compound according to claim 1.

25. A compound of the formula: ##STR21## in which: Q is --OH or --NH.sub.2;

A is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, or --S--;
--Ar-- is a divalent aromatic ring;
W is --CO-- or --SO.sub.2 --;
n has a value of from 0 to 4,
* designates a chiral center in the L configuration; and
J is an amino acid residue of glucine, D-aspartic acid, D-proline, or D-homogysteic acid which residue is linked through the.alpha.-amino group.

26. A compound according to claim 25 in which

A is --CH.sub.2 --,
--Ar-- is phenylene or thienediyl;
W is --CO--;
n has a value of 2, and
J is D-aspartic acid linked through its.alpha.-amino group.

29. A compound of the formula: ##STR22## in which: Q is --OH or --NH.sub.2;

A is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, or --S--;
--Ar-- is a divalent aromatic ring; and
W is --CO-- or --SO.sub.2 --.

30. A compound according to claim 29 in which Q is hydroxy, and W is --CO--.

Referenced Cited
U.S. Patent Documents
4684653 August 4, 1987 Taylor et al.
4818819 April 4, 1989 Taylor et al.
4889859 December 26, 1989 Taylor et al.
4895946 January 23, 1990 Taylor et al.
5008391 April 16, 1991 Barnett et al.
5144012 September 1, 1992 Johnson et al.
5159079 October 27, 1992 Pearce et al.
Foreign Patent Documents
91304757 May 1991 EPX
07082174-A March 1995 JPX
Other references
  • Bisset et al., "Quinazoline Antifolates Inhibiting Thymidylate Synthase: Synthesis and Biological Activity of .gamma.-Linked Peptide and Amide Analogues of 2-Desamino-2-Methyl-N10-Propargyl-5,8,-Dideazafolic Acid (ICI 198583)", Tenth International Symposium, Chemistry and Biology of Pteridines and Folates, Orange Beach, Alabama, Final Program and Abstract Book, p. 135 (Mar. 21-26, 1993). Habeck et al., "A Novel Class of Monoglutamated Antifolates Exhibits Tight-binding Inhibiton of Human Glycinamide Ribonucleotide Formyltransferase and Potent Activity against Solid Tumors", Cancer Research, 54, pp. 1021-1026 (Feb. 15, 1994). Howbert et al., "Novel Agents Effective against Solic Tumors: The Diarylsulfonylureas. Synthesis, Activities, and Analysis of Quantitative Structure-Activity Relationships", J. Med. Chem., 33:9, pp. 2393-2407 (1990). Kaminski, "2-Chloro-4,6-dimethoxy-1,3,5-triazine. A New Coupling Reagent for Peptide Synthesis", Communications, pp. 917-920 (1987). Rosowsky et al., "Methotrexate Analogues. 20. Replacement of Glutamate by Longer-Chain Amino Diacids: Effects on Dihydrofolate Reductase Inhibition, Cytotoxicity, and in Vivo Antitumor Activity", J. Med. Chem., 36:13, pp. 1719-1724 (1983). Rosowsky et al., "Side Chain Modified 5-Deazafolate and 5-Deazatetrahydrofolate Analogues as Mammalian Folypolyglutamate Synthetase and Glycinamide Ribonucleotide Formyltransferase Inhibitors: Synthesis and in Vitro Biological Evaluation", J. Med. Chem., 35:9, pp. 1578-1588 (1992). Singh et al., "Synthesis and Biological Evaluation of N.sup..varies. -(5-Deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine", J. Med. Chem., 35:11, pp. 2002-2006 (1992). Stephens et al., "Use of Murine L5178Y Lynphome Thymidine Kinase (TK) Mutants for In Vitro and In Vivo Antitumour Efficacy Evaluation of Novel Thymidylate Synthase (TS) Inhibitors", Tenth International Symposium, Chemistry and Biology of Pteridines and Folates, Orange Beach, Alabama, Final Program and Abstract Book, p. 134 (Mar. 21-26, 1993).
Patent History
Patent number: 5786358
Type: Grant
Filed: Sep 4, 1996
Date of Patent: Jul 28, 1998
Assignee: The Trustees of Princeton University (Princeton, NJ)
Inventors: Chuan Shih (Carmel, IN), Lynn S. Gossett (Indianapolis, IN), William J. Gill (Indianapolis, IN), Edward C. Taylor (Princeton, NJ), James T. Metz (Indianapolis, IN)
Primary Examiner: Mukund J. Shah
Assistant Examiner: Brenda Coleman
Law Firm: Mathews, Collins, Shepherd & Gould, P.A.
Application Number: 8/708,351
Classifications
Current U.S. Class: 514/258; Three Ring Nitrogens In The Bicyclo Ring System (544/279)
International Classification: C07D47102; A61K 31505;